The GIST is at the bottom right of the page.
Geoff’s narrations are coming
Three months ago, Health Rising reported on the Simmaron Research Foundation’s Rapamycin ME/CFS clinical trial. It’s already time for an update—Simmaron’s research team moves fast.
A Little Background
The mTORC1 complex.
Seeking to create a mouse model for chronic fatigue syndrome (ME/CFS), the team gave mice a compound that inhibited autophagy, a cellular cleanup process crucial to mitochondrial functioning. When autophagy breaks down, it can impair oxygen consumption and mitochondrial activity, affect immune functioning, turn cells into pro-inflammatory generators, and lead to clumps of proteins that can damage all sorts of cellular processes.
The mice responded with high levels of a product called ATG13. Increased ATG13 levels are usually associated with increased autophagy but can also be the result of a compensatory response to a downstream blockade of autophagy. Indeed, the mice responded by looking like they had ME/CFS. Interestingly, the female mice were much more likely to become ill, quickly became fatigued when asked to exercise, and their grip strength declined.
Moving to humans, the Simmaron team found high ATG13 levels in the serum of ME/CFS patients. Then, when the serum was applied to cultured microglial cells, it appeared that the cells’ mitochondria had indeed imploded. Clearly tweaked by something, the microglial cells spewed out free radicals and produced inflammatory factors.
Further study suggested that the high ATG13 levels in the ME/CFS patients were activating receptors on the microglial cells called RAGE, which trigger signaling cascades in cells that cause inflammation and the generation of reactive oxygen species (ROS). This seems to be a nice fit for the microglial hypersensitivity problem that appears to be present in ME/CFS and could be affecting many symptoms.
When an antibody to neutralize ATG13 was applied to the serum and the microglia didn’t respond so negatively, the Simmaron researchers concluded that high ATG13 levels were the culprit.
With autophagy as a target, enter a drug – rapamycin (Rapumune, sirolimus) – that can upregulate autophagy and, if I have it right, clean up the damaged proteins and organelles produced by the upregulation of RAGE. Rapamycin may also be able to reduce RAGE activation.
Phase I Trial Update
The Rapamycin clinical trials team.
I recently communicated with Simmaron Research Foundation CEO and Translational Science chief Gunnar Gottschalk, Ph.D., about the Rapamycin (Rapamune, sirolimus) trial. (Gottschalk is the primary investigator for the trial, and David Kaufman, MD, is the clinical trial lead.) With most of the Phase I trial complete, Gottschalk was able to talk about some of the preliminary results.
The phase I trial used a variety of questionnaires (MFI, SF-36, sleep questionnaire, symptom inventory, Bell Activity Scale) to assess symptoms and functionality, a biomarker for autophagy activity called beclin-1, and some lab tests to assess safety (CBC w Diff, Chem 14, Lipid panel, Hemoglobin A1C, HS-CRP).
The study aimed to raise autophagy levels to increase energy production, reduce inflammation, and improve symptoms.
Differing dose regimens were used. I didn’t see the starting dose, but it may have been 5mg, after which doses were ramped up from 1-6 mg/week, depending on the patient.
The participants were assessed two weeks before the trial started, six weeks after taking Rapamycin (on a ramping-up dosing schedule), and then 30 and 60 days later. The patients were stratified according to onset type, duration, disability, and gender. There is no placebo-control group.
Results
Rapamycin ME/CFS Pilot Study.
Gunnar reported that with most of the results in, a significant percentage of patients were considered responders. He stated that the responders “were seeing a significant number of changes in key symptoms, including reductions in PEM, improved energy, and reduced brain fog.
THE GIST
- Just a few months ago, Health Rising posted a blog on the SImmaron Research Foundation’s rapamycin clinical trial for ME/CFS. Simmaron has been moving fast: the Phase I part of the trial is almost complete, and with good results in hand – and with half the funding they need – they’re moving to a larger Phase II trial.
- The trial tested the idea that a drug called rapamycin – which is being investigated in longevity circles- might be able to restore a process called autophagy in ME/CFS.
- Autophagy is a cleanup process cells use to vacuum up damaged mitochondria and other organelles. Problems with autophagy can lead to problems with energy production, inflammation and other issues.
- Simmaron’s mice, culture, and human studies suggested that impaired autophagy in ME/CFS had resulted in increased levels of oxidative stress and inflammation.
- The Phase I rapamycin trial assessed the ability of rapamycin (in varying doses) to improve symptoms and autophagy functioning (using a factor called beclin-1).
- Gunnar Gottschalk, the primary investigator, reported that with most of the results in, a significant percentage of patients were considered responders. He stated that the responders “were seeing a significant number of changes in key symptoms, including reductions in PEM, improved energy, and reduced brain fog.
- Rapamycin has also produced a significant improvement in autophagy activity, which was associated with a significant improvement in the multidimensional fatigue inventory (MFI), suggesting that improvements in autophagy resulted in improvements in fatigue.
- While others benefited, it appears people with viral disease onset (EBV, CMV, HHV-6) or SARs-CoV-2 (coronavirus) responded best, and Simmaron will focus on this subset in the Phase II trial.
- With the good results from the Phase I trial, Simmaron is moving forward with a more extensive Phase II trial, which will increase the dosage by about a third (see blog for details). The trial is open to the patients of the physicians participating in it.
- The new trial will also include an antibody test developed by Simmaron in conjunction with Thermo Scientific to provide a more accurate assessment of the mTORC1 pathway being targeted.
- The researchers are seeking FDA approval by developing a diagnostic panel using two factors ( pATG13, BECLIN-1) that predict who will benefit from the drug.
- Simmaron is looking for more funding to complete the phase II trial.
- Note that a PolyBio-funded long COVID rapamycin trial, which assesses different factors, is also underway.
Right now, it appears people with viral disease onset (EBV, CMV, HHV-6) or SARs-CoV-2 (coronavirus) are responding best, and Simmaron will focus on this subset in the Phase II trial. They see responses in people with other subsets (autoantibodies, MCAS, etc.) but not as frequently.
They expect a preprint of the Phase I trial results to be published within a few months.
Phase II Trial
With the good results from the Phase I trial, Simmaron is using its recent strategic partnership with AgelessRx to move forward with a more extensive Phase II trial. (With about half the funding needed for the trial in hand, they have started enrolling patients and are attempting to raise the remaining funds. The trial is open by invitation only to the patients of the physicians participating in it.)
The Phase II trial will be different in a number of ways. For one, instead of using Rapamycin from other sources, they are switching to a compounded generic (Dr. Reddy’s®) from AgelessRx to ensure everyone gets the drug with the same bioavailability. They will also use two standardized dose regimens which will increase the total dose of the drug by about a third.
Dose – two options:
- start with 5mg – increase by 5mg/week for 3 weeks = 20 mg at end.
- start with 5 mg – increase by 2.5 mg over 6 weeks = 20 mg by end.
The trial will also include new questionnaires (the DePaul Symptom Questionnaire and a functional capacity questionnaire called Funcap).
hCG F <50, insulin, and Quant sirolimus plasma will be added to the lab tests. Plus, DNA samples or cheek swabs will be saved for future CYP43A/Cytochrome P450 genetic analysis (fast vs slow metabolizers).
More significantly, a new antibody that Simmaron developed with Thermo Scientific for pATG13 will be included. This antibody will provide the most accurate assessment of the mTORC1 pathway the team has found to be upregulated in ME/CFS.
They will also utilize mobile phlebotomy to gather blood samples.
FDA Approval the Goal
Simmaron has already found 130 age and gender-matched healthy controls over the past year, but they are not including a placebo arm in this trial because they’re seeking FDA approval for the drug in ME/CFS in another way.
They aim to develop a diagnostic panel using pATG13 and BECLIN-1 to predict who responds to Rapamycin. They’re using a “high-complexity lab” called Coppe Labs (Konstance Knox, PhD), which specializes in the development of FDA diagnostic panels.
(If I have it right, if the clinical trials go as hoped, people with high pATG13 (blocks the MTORC1 pathway, which upregulates autophagy) and low BECLIN-1 levels (indicating low autophagy) will probably fit this profile). Ultimately, general practitioners will be able to order these labs to determine which patients should try the drug.
If Simmaron is successful, this will be the first time that patients who are likely to benefit from a treatment have been biologically identified. That’s a big deal in a heterogeneous disease in which patients and practitioners often engage in lengthy searches for something that helps.
Simmaron is looking for more funding to complete the Phase II trial.
Right now, Gunnar Gottschalk and Avik Roy are working on an application for a rare ROI NIH ME/CFS grant. Getting one would be a stunning success for the Simmaron Research team, but they’ve laid the groundwork well. They started with mouse studies, moved into humans, and validated their findings in numerous ways.
PolyBio Long Rapamycin Trial Also Underway
A model of Rapamycin latching onto mTORC1 and preventing it from activating.
Long COVID has its Rapamycin trial. The $800,000 trial at David Putrino’s new CoRE clinic, funded by the PolyBio Foundation, is determining how Rapamycin may affect immune and hormonal functioning and symptoms. It’s possible that Rapamycin, for instance, could be helpful with the T-cell exhaustion that’s shown up in both ME/CFS and long COVID. Dr. Putrino, the clinical lead, stated, “We are hopeful that this will be a first step in validating a cheap, safe, and effective long COVID treatment.”
With two Rapamycin trials underway, we should learn a lot about what Rapamycin does in these diseases and what kinds of patients it may help.
